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1.
PLoS Genet ; 18(6): e1010260, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35727838

RESUMO

The shelterin protein POT1 has been found mutated in many different familial and sporadic cancers, however, no mouse models to understand the pathobiology of these mutations have been developed so far. To address the molecular mechanisms underlying the tumorigenic effects of POT1 mutant proteins in humans, we have generated a mouse model for the human POT1R117C mutation found in Li-Fraumeni-Like families with cases of cardiac angiosarcoma by introducing this mutation in the Pot1a endogenous locus, knock-in for Pot1aR117C. We find here that both mouse embryonic fibroblasts (MEFs) and tissues from Pot1a+/ki mice show longer telomeres than wild-type controls. Longer telomeres in Pot1a+/ki MEFs are dependent on telomerase activity as they are not found in double mutant Pot1a+/ki Tert-/- telomerase-deficient MEFs. By using complementation assays we further show that POT1a pR117C exerts dominant-negative effects at telomeres. As in human Li-Fraumeni patients, heterozygous Pot1a+/ki mice spontaneously develop a high incidence of angiosarcomas, including cardiac angiosarcomas, and this is associated to the presence of abnormally long telomeres in endothelial cells as well as in the tumors. The Pot1a+/R117C mouse model constitutes a useful tool to understand human cancers initiated by POT1 mutations.


Assuntos
Hemangiossarcoma , Complexo Shelterina/metabolismo , Telomerase , Proteínas de Ligação a Telômeros/metabolismo , Animais , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Hemangiossarcoma/genética , Humanos , Síndrome de Li-Fraumeni , Camundongos , Mutação , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo , Proteínas de Ligação a Telômeros/genética
2.
Nat Commun ; 11(1): 1168, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127537

RESUMO

Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc-/-) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc-/- livers. Treatment of G2-Terc-/- mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc-/- mice also decreases longevity, in contrast to lifespan extension in single S6K1-/- female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres.


Assuntos
Envelhecimento/genética , RNA/genética , Serina-Treonina Quinases TOR/metabolismo , Telomerase/genética , Telômero/genética , Envelhecimento/efeitos dos fármacos , Animais , Dano ao DNA/efeitos dos fármacos , Feminino , Longevidade/efeitos dos fármacos , Longevidade/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/genética , Fosforilação , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Sirolimo/farmacologia , Taxa de Sobrevida , Serina-Treonina Quinases TOR/genética , Telômero/efeitos dos fármacos , Telômero/metabolismo
3.
PLoS One ; 13(10): e0204909, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30307978

RESUMO

RAP1, a component of the telomere-protective shelterin complex, has been shown to have both telomeric and non-telomeric roles. In the liver, RAP1 is involved in the regulation of metabolic transcriptional programs. RAP1-deficient mice develop obesity and hepatic steatosis, these phenotypes being more severe in females than in males. As hepatic steatosis and obesity have been related to increased liver cancer in mice and humans, we set out to address whether RAP1 deficiency resulted in increased liver cancer upon chemical liver carcinogenesis. We found that Rap1-/- females were more susceptible to DEN-induced liver damage and hepatocellular carcinoma (HCC). DEN-treated Rap1-/- female livers showed an earlier onset of both premalignant and malignant liver lesions, which were characterized by increased abundance of γH2AX-positive cells, increased proliferation and shorter telomeres. These findings highlight an important role for RAP1 in protection from liver damage and liver cancer.


Assuntos
Carcinoma Hepatocelular/genética , Dietilnitrosamina/efeitos adversos , Histonas/metabolismo , Neoplasias Hepáticas/genética , Proteínas rap1 de Ligação ao GTP/genética , Idade de Início , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/mortalidade , Fatores Sexuais , Encurtamento do Telômero
4.
Aging Cell ; 13(4): 656-68, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24725274

RESUMO

TRF2 is a component of shelterin, the protein complex that protects the ends of mammalian chromosomes. TRF2 is essential for telomere capping owing to its roles in suppressing an ATM-dependent DNA damage response (DDR) at chromosome ends and inhibiting end-to-end chromosome fusions. Mice deficient for TRF2 are early embryonic lethal. However, the role of TRF2 in later stages of development and in the adult organism remains largely unaddressed, with the exception of liver, where TRF2 was found to be dispensable for maintaining tissue function. Here, we study the impact of TRF2 conditional deletion in stratified epithelia by generating the TRF2(∆/∆) -K5-Cre mouse model, which targets TRF2 deletion to the skin from embryonic day E11.5. In marked contrast to TRF2 deletion in the liver, TRF2(∆/∆) -K5-Cre mice show lethality in utero reaching 100% lethality perinataly. At the molecular and cellular level, TRF2 deletion provokes induction of an acute DDR at telomeres, leading to activation of p53 signaling pathways and to programed cell death since the time of Cre expression at E11.5. Unexpectedly, neither inhibition of the NHEJ pathway by abrogation of 53BP1 nor inhibition of DDR by p53 deficiency rescued these severe phenotypes. Instead, TRF2 deletion provokes an extensive epidermal cell death accompanied by severe inflammation already at E16.5 embryos, which are independent of p53. These results are in contrast with conditional deletion of TRF1 and TPP1 in the skin, where p53 deficiency rescued the associated skin phenotypes, highlighting the comparatively more essential role of TRF2 in skin homeostasis.


Assuntos
Envelhecimento/metabolismo , Homeostase , Pele/metabolismo , Telômero/metabolismo , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Animais , Apoptose , Proteínas Cromossômicas não Histona/deficiência , Proteínas Cromossômicas não Histona/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Perda do Embrião/metabolismo , Perda do Embrião/patologia , Desenvolvimento Embrionário , Epiderme/metabolismo , Epiderme/patologia , Epitélio/metabolismo , Epitélio/patologia , Deleção de Genes , Integrases/metabolismo , Queratina-5/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , Pele/embriologia , Pele/patologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Homeostase do Telômero , Proteínas de Ligação a Telômeros , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53
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